An international team of researchers has identified genetic mutations that cause severe, difficult to treat form of childhood epilepsy. Some mutations disrupt the operation of the synapse, the highly dynamic union in which nerve cells communicate with each other.
Multiple US and European researchers have conducted a research, the largest collaborative study to date, focused on the genetic roots of severe epilepsies. The scientists published their findings in the American Journal of Human Genetics (available onlinein Epub format).
The current study adds to the list of mutations of genes previously reported to be associated with these serious epileptic syndromes, called epileptic encephalopathies. The researchers sequenced the exome (those portions of DNA that code for proteins) of 356 patients with severe childhood epilepsy, as well as their parents. Scientists sought “de novo” mutations – those that emerged in affected children but not their parents. Altogether 429 such mutations were identified as the novo.
In 12 percent of children, it was considered that these mutations unequivocally caused epilepsy in the child. In addition to several known genes of childhood epilepsy, the study team found strong evidence of additional new genes, many of which are involved in synapse function.
Epilepsy is among the most common disorders of the central nervous system, affecting up to 3 million patients in the USA alone. Up to a third of all epilepsies are resistant to treatment with antiepileptic drugs and may be associated with other disabilities such as autism and intellectual impairment. Severe epilepsies are particularly devastating in children.
The research teams used a method called exome sequencing, which is seen in the human genome that carries the blueprints of proteins. By comparing the sequence information in children with epilepsy with that of their parents, the researchers were able to identify changes that arose de novo in the genomes of affected children. While de novo changes are increasingly recognized as the genetic cause of severe seizure disorders, not all changes are necessarily a cause de novo disease.
The most striking finding in the study by this international research group is a gene called DNM1, which was found mutated in five patients. The gene carries the code for dynamin-1, a structural protein that plays a role in small vesicles shuttling between the body of the neuron and synapse. These vesicles are structures containing neurotransmitters crucial chemical signals for communication between nerve cells. When the researchers looked at the network level, they found that many of the genes found to be mutated in patients had a clear relationship to the function of the synapse.
A spokesman for Citizens United for Research in Epilepsy (CURE), a nonprofit organization dedicated to finding a cure for epilepsy and increasing disease awareness organization, applauded the study. Dr. Tracy Dixon-Salazar, Associate Director of Research CURE and mother of a child with severe genetic epilepsy, she added: It is exciting to see big corporations put genomic data from nearly 400 patients together. This clearly shows that working together we can find new genes faster, which will help us explain why this is often a devastating disease in children.